Submissions for variant NM_000546.6(TP53):c.464C>A (p.Thr155Asn)

dbSNP: rs786202752

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473602	SCV000545261	pathogenic	Li-Fraumeni syndrome	2024-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 155 of the TP53 protein (p.Thr155Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 8308926, 28356770; internal data). ClinVar contains an entry for this variant (Variation ID: 406564). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492645	SCV000581130	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-13	criteria provided, single submitter	clinical testing	The p.T155N pathogenic mutation (also known as c.464C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 464. The threonine at codon 155 is replaced by asparagine, an amino acid with similar properties. This alteration has been detected in several individuals meeting the revised Chompret criteria (Kyritsis A et al. J. Natl. Cancer Inst. 1994 Mar; 86(5):344-9; Nandikolla A et al. Breast Cancer (Dove Med Press) 2017; 9 207-215; Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have a loss of transactivation in yeast-based assays (Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Smardova J et al. Oncol. Rep. 2016 Mar;35:1859-67). Studies conducted in human cell lines indicate this alteration has dominant-negative activity and is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The threonine at codon 155 is a target of phosphorylation, which may be an important regulatory step for maintaining appropriate levels of p53 protein in the cell (Bech-Otschir D et al. EMBO J. 2001 Apr; 20(7):1630-9). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV002269272	SCV002553144	likely pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and dominant negative effect (Monti 2011, Giacomelli 2018, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with TP53-related cancers (Kyritsis 1994, Nandikolla 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29979965, 15510160, 26718964, 25149524, 15781632, 32850382, 30840781, 17606709, 21343334, 30224644, 28356770, 24113472, 8308926, 32321992, 30720243)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000473602	SCV002556080	likely pathogenic	Li-Fraumeni syndrome	2022-06-02	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.464C>A (p.Thr155Asn) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes. In addition to being widely reported in a variety of somatic cancers, c.464C>A has been reported in the literature as a reportedly germline variant in settings of glioma and breast cancer and (example, Kyritsis_1994, Nandikolla_2017). At least one publication reports experimental evidence evaluating an impact on protein function (example, Kato_2003). The most pronounced variant effect results in non-functional outcome based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV004022603	SCV004930560	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506226	SCV000602271	uncertain significance	not specified	2017-01-19	flagged submission	clinical testing